Pharmaceutical foam

ABSTRACT

The present invention provides various pharmaceutically active topical delivery compositions. In particular, compositions of the present invention are present in a pressurized container comprising a quick-breaking alcoholic foaming agent, such that when the composition is released, i.e., dispensed, from the pressurized container, a quick-breaking temperature sensitive foam is formed. In addition, the present invention provides various aspects related to such compositions, including methods for modulating a foam characteristic, methods for improving the shelf-life of a pharmaceutically active compound, methods for the percutaneous treatment of various diseases, infections, and illnesses, and methods for evaluating foam characteristics.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.10/763,379, filed Jan. 23, 2004, which application claims priority toU.S. Provisional Application Nos. 60/442,280, filed Jan. 24, 2003 and60/454,832, filed Mar. 13, 2003, the teachings all of which areincorporated herein by reference in their entireties for all purposes.

FIELD OF THE INVENTION

The present invention relates to topical delivery of at least onepharmaceutically active compound, especially clindamycin or itspharmaceutically acceptable salt or a prodrug thereof, alone or incombination with another pharmaceutically active compound.

BACKGROUND OF THE INVENTION

There are many challenges in the topical application of pharmaceuticallyactive agents. One major objective is to achieve percutaneouspenetration of the active agent to the site of treatment. Thecomposition should also have desirable cosmetic characteristics.Application should be easy, smooth, and should not leave a noticeableresidue on the surface of the skin. Moreover, the composition should notcause irritation, discomfort, or inconvenience.

Many antifungal and antibacterial agents are used topically to treatepidermal infections. Some antibiotics, such as tetracycline andclindamycin, are also used to treat acne and other skin diseases thatare caused, directly or indirectly, by bacteria. One of the side-effectsof systemically administered clindamycin is colitis, which can bedangerous and even fatal. Thus, in treating acne, it is desirable toadminister clindamycin topically. Cleocin T®, manufactured byPharmacia-Upjohn, contains clindamycin phosphate, which is inactive invitro, but is hydrolyzed in vivo to the antibacterially activeclindamycin. Cleocin T® is currently available as a gel, a lotion, and atopical solution, and is used for topical treatment of acne vulgaris.

Lotion and gel topical dosage forms have the disadvantage of extendedrub-in and may leave oily residues. The solution form readily runs offthe site of application, and therefore it is difficult to applycontrolled amounts using the solution form.

The present invention overcomes these disadvantages by providing acomposition having at least one pharmaceutically active compound, whichis useful for topical administration as described herein, as a foam thatis a non-runny, easy to apply, and uses a low residue vehicle. When thefoam is applied, body heat causes the foam structure to break down anddeposit the active ingredient(s) in the form of a vehicle resembling asolution. The foam composition provides good control of the applicationof a small amount of product to the desired area.

SUMMARY OF THE INVENTION

The present invention overcomes the disadvantages of the prior art byproviding a pharmaceutically active composition, which is useful fortopical administration, as a foam that is a non-runny, easy to apply,and uses a low residue vehicle. Surprisingly, the foam compositions ofthe present invention provide enhanced delivery of an active compound(s)across the skin compared to gel compositions and without the concomitantdisadvantages associated with solution formulations (e.g., runniness,difficulty in applying controlled amounts).

As such, in one aspect, the present invention provides a topicaldelivery composition in a pressurized container comprising:

-   -   up to 15% w/w of at least one pharmaceutically active compound,        or its pharmaceutically acceptable salt or a prodrug thereof;    -   from about 83% to about 97.9% w/w of a quick-breaking foaming        agent; and    -   from about 2% to about 7% w/w of an aerosol propellant selected        from the group consisting of a hydrocarbon, a        chlorofluorocarbon, dimethyl ether, hydrofluorocarbons and a        mixture thereof,    -   wherein the composition is a quick-breaking temperature        sensitive foam after release from the container.

In one embodiment, the quick-breaking foaming agent comprises a C₁-C₆alcohol and water. In a preferred embodiment, the quick-breaking foamingagent comprises a C₁-C₆ alcohol, a C₁₄-C₂₂ alcohol, water, and asurfactant. In another embodiment, the quick-breaking foaming agent doesnot contain a C₁-C₆ alcohol. In some embodiments, the quick-breakingfoaming agent can also comprise an emollient, which can also act as ahumectant. In addition, the quick-breaking foaming agent can alsocomprise a pH adjusting agent.

In one particular embodiment, the at least one pharmaceutically activecompound is an antibiotic agent. Preferred antibiotic agents includeclindamycin or a pharmaceutically acceptable salt or ester thereof. Aparticularly preferred antibiotic agent is clindamycin phosphate, whichis inactive in vitro, but hydrolyzes in vivo to the antibacteriallyactive clindamycin.

In another aspect, the at least one pharmaceutically active compoundcomprises a combination of active agents. Any combination of activeagents suitable for topical administration can be used in thecompositions of the present invention. Preferably, the combination ofactive agents comprises at least two agents selected from an antibioticagent, an antifungal agent, a retinoid (e.g., tretinoin, tazarotene), aretinoid derivative (e.g., adapalene), salicylic acid, azelaic acid,sodium sulfacetamide, and benzoyl peroxide. Suitable antibiotic agentsinclude, but are not limited to, clindamycin, erythromycin,tetracycline, minocycline, doxycycline, pharmaceutically acceptablesalts thereof, and prodrugs thereof. More preferably, the combination ofactive agents comprises clindamycin phosphate and a member selected froman antifungal agent, a retinoid (e.g., tretinoin, tazarotene), aretinoid derivative (e.g., adapalene), salicylic acid, azelaic acid,sodium sulfacetamide, benzoyl peroxide, another antibiotic (e.g.,erythromycin, tetracycline, minocycline, doxycycline), and mixturesthereof. In a particularly preferred embodiment, the at least onepharmaceutically active compound comprises a combination of clindamycinphosphate and tretinoin. In another particularly preferred embodiment,the at least one pharmaceutically active compound comprises acombination of clindamycin phosphate and benzoyl peroxide.

Compositions of the present invention comprising a combination of activeagents preferably contain an effective amount of each agent, e.g.,between about 0.01% to about 10% of an antibiotic, preferably betweenabout 0.1% to about 5% of an antibiotic, any effective amount ofsalicylic acid or benzoyl peroxide, preferably between about 0.5% toabout 10% w/w, and any effective amount of a retinoid or a retinoidderivative, preferably between about 0.01% to about 0.5% w/w. However,concentrations of each agent above or below the effective amount arealso within the scope of the present invention.

In another embodiment, the pharmaceutically active compound is anantifungal agent. Preferred antifungal agents include ketoconazole,e.g., in the form of Nizoral®. In a further embodiment, thepharmaceutically active compound comprises a combination of anantifungal agent and an agent selected from an antibiotic agent, aretinoid (e.g., tretinoin, tazarotene), a retinoid derivative (e.g.,adapalene), salicylic acid, azelaic acid, sodium sulfacetamide, benzoylperoxide, and mixtures thereof. Suitable antibiotic agents include, butare not limited to, clindamycin, erythromycin, tetracycline,minocycline, doxycycline, pharmaceutically acceptable salts thereof, andprodrugs thereof.

In yet another aspect, the present invention provides a method formodulating the foam breaking temperature of a quick-breaking temperaturesensitive foam composition. In one particular embodiment, the foambreaking temperature is modulated by, for example, changing the C₁-C₆alcohol to water ratio in the quick-breaking temperature sensitive foamcomposition.

In still yet another aspect, the present invention provides a method forthe percutaneous treatment of acne, using, for example, the compositionsof the present invention. The acne treatment method generally involvesapplying a quick-breaking temperature sensitive foam compositioncomprising an effective amount of clindamycin or a pharmaceuticallyacceptable salt or a prodrug thereof to a subject in need of suchtreatment. In a preferred embodiment, the quick-breaking temperaturesensitive foam composition further comprises a retinoid (e.g.,tretinoin, tazarotene). Preferably, the retinoid is present in an amountof from about 0.01% to about 0.1% w/w. In another preferred embodiment,the quick-breaking temperature sensitive foam composition furthercomprises benzoyl peroxide. Preferably, the benzoyl peroxide is presentin an amount of from about 0.5% to about 10% w/w.

In a further aspect, the present invention provides a method forevaluating foam characteristics, the method comprising:

-   -   providing a visual aid comprising a depiction of various foam        structures;    -   dispensing a quick-breaking temperature sensitive foam        composition from a pressurized container comprising a        quick-breaking foaming agent and a propellant; and    -   evaluating the foam structure using the visual aid.

In still yet a further embodiment, the present invention provides a useof a pharmaceutical composition in a pressurized container in thepreparation of a medicament for the percutaneous treatment of acne, thecomposition comprising:

-   -   up to 15% w/w of at least one pharmaceutically active compound,        or its pharmaceutically acceptable salt or a prodrug thereof;    -   from about 83% to about 97.9% w/w of a quick-breaking foaming        agent; and    -   from about 2% to about 7% w/w of an aerosol propellant selected        from the group consisting of a hydrocarbon, a        chlorofluorocarbon, dimethyl ether, hydrofluorocarbons and a        mixture thereof,    -   wherein the composition is a quick-breaking temperature        sensitive foam after release from the container.

These and other objects, advantages, and embodiments will become moreapparent when read with the detailed description and drawings thatfollow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the effect of temperature on the clindamycinphosphate foam structure, which was determined by first dispensingapproximately 2 grams of foam at 20° C. The foam was then placed in acontrolled environment at the indicated temperatures and the timerequired to melt the foam to a liquid was determined.

FIG. 2 shows one embodiment of a visual aid that can be used inevaluating foam structures.

FIG. 3 is a graph showing the amount of clindamycin phosphatedegradation at various pH and citrate buffer levels as described inExample 1.

FIG. 4 is a graph showing the amount of clindamycin phosphate remainingat various times under various pH levels in cans at varioustemperatures.

FIG. 5 shows stability data of clindamycin phosphate as determined inExample 4.

FIG. 6 shows plasma clindamycin concentration as a function of timeafter application of clindamycin foam and ClindaGel™.

FIG. 7 shows a graph of the cumulative percutaneous absorption ofclindamycin foam, ClindaGel™, and Cleocin T® solution over a 24-hourperiod. Each time-point represents the mean total absorption ±standarderror for 3 skin donors (3 replicates for each). * p<0.05 (gel vs.foam); p<0.06 (gel vs. solution); p>0.1 (foam vs. solution).

FIG. 8 shows a graph of the flux profile for the percutaneous absorptionof clindamycin foam, ClindaGel™, and Cleocin T® solution over a 24-hourperiod. Each time-point represents the mean absorption ±standard errorfor 3 skin donors (3 replicates for each).

FIG. 9 shows a graph of the distribution of clindamycin in differentlayers of the skin 24 hours after application of clindamycin foam,ClindaGel™, and Cleocin T® solution.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Unless the context requires otherwise, the terms “active agent”, “activecompound,” “at least one pharmaceutically active compound” and“pharmaceutically active agent” are used interchangeably herein andrefer to a substance having a pharmaceutical, pharmacological ortherapeutic effect.

“Homogeneous” means uniform throughout, i.e., a single phase mixture.

“Pharmaceutically acceptable salt” of an active compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthmetal ion, or an aluminum ion; or coordinates with an organic base suchas ethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

“Prodrug” refers to any compound which releases an active agent in vivowhen such prodrug is administered to a subject. Prodrugs of an activeagent are prepared by modifying one or more functional group(s) presentin the active agent in such a way that the modification(s) may becleaved in vivo to release the parent compound. Prodrugs includecompounds wherein a hydroxy, amino or sulfhydryl group in the activeagent is bonded to any group, e.g., protecting group, that may becleaved in vivo to regenerate the free hydroxyl, amino or sulfhydrylgroup, respectively. Examples of prodrugs include, but are not limitedto, active agents whose functional group(s) are protected by one or moreprotecting groups listed in T. W. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) edition, John Wiley & Sons, NewYork, 1999, and Harrison and Harrison et al., Compendium of SyntheticOrganic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996), which areincorporated herein by reference in their entirety. Representativehydroxy protecting groups which are useful in preparing prodrugs includeacyl groups (e.g., formyl, acetyl and trifluoroacetyl), alkyl ethers,phosphate ethers, phosphate esters, and the like. Representative aminoprotecting groups that are useful in preparing prodrugs include acylgroups (e.g., formyl, acetyl, and trifluoroacetyl), benzyloxycarbonyl(CBZ), tert-butoxycarbonyl (Boc), and the like.

The terms “antibiotic” and “antibacterial” are used hereininterchangeably to refer to a compound that inhibits the growth of,inhibits the virulence of, or kills bacterial cells. Antibioticsinclude, e.g., substances produced by various species of microorganisms(e.g., bacteria, fungi, and actinomycetes), variants thereof, andsynthetic antibacterial agents. A complete list of antibiotics is toolong to be included herein, and those of skill in the art are aware ofthe multitude of antibiotics that can be used in the present invention.See, e.g., Chambers and Sande, Antimicrobial Agents: GeneralConsiderations in Goodman & Gilman's The Pharmacological Basis ofTherapeutics, Hardman and Limbard eds., (1996); and Kucers, et al., TheUse of Antibiotics: A Clinical Review of Antibacterial, Antifungal, andAntiviral Drugs Oxford Univ. Press (1997). Suitable antibiotic agentsinclude, but are not limited to, clindamycin, erythromycin,tetracycline, minocycline, doxycycline, penicillin, ampicillin,carbenicillin, methicillin, cephalosporins, vancomycin, and bacitracin,streptomycin, gentamycin, chloramphenicol, fusidic acid, ciprofloxin andother quinolones, sulfonamides, trimethoprim, dapsone, isoniazid,teicoplanin, avoparcin, synercid, virginiamycin, cefotaxime,ceftriaxone, piperacillin, ticarcillin, cefepime, cefpirome, rifampicin,pyrazinamide, ciprofloxacin, levofloxacin, enrofloxacin, amikacin,netilmycin, imipenem, meropenem, inezolid, pharmaceutically acceptablesalts thereof, and prodrugs thereof. Preferably, the antibiotic agent isclindamycin, erythromycin, tetracycline, minocycline, doxycycline,pharmaceutically acceptable salts thereof, or prodrugs thereof. Morepreferably, the antibiotic agent is clindamycin, or a pharmaceuticallyacceptable salt or a prodrug thereof.

“Vehicle” refers to a composition which has only excipient or componentsrequired to carry an active agent, but which itself has nopharmaceutical or therapeutic effect.

The term “fatty alcohol” refers to C₁₄-C₂₂ alcohol(s).

The term “pH” is defined as the value given by a suitable, properlystandardized pH meter using an appropriate electrode.

II. General

The present invention provides various pharmaceutically active topicaldelivery compositions. In one embodiment, a topical delivery compositionin a pressurized container comprises: up to 15% w/w of at least onepharmaceutically active compound, or its pharmaceutically acceptablesalt or a prodrug thereof; from about 83% to about 97.9% w/w of aquick-breaking foaming agent; and from about 2% to about 7% w/w of anaerosol propellant selected from the group consisting of a hydrocarbon,a chlorofluorocarbon, and a mixture thereof, wherein the composition isa quick-breaking temperature sensitive foam after release from thecontainer.

In a preferred embodiment, the compositions of the present invention arepresent in a pressurized container comprising a homogeneous mixture of:from about 0.1% to about 10% w/w of a pharmaceutically active compound,or its pharmaceutically acceptable salt or a prodrug thereof; from about83% to about 97.9% w/w of a quick-breaking foaming agent; and from about2% to about 7% w/w of an aerosol propellant selected from the groupconsisting of a hydrocarbon, a chlorofluorocarbon, and a mixturethereof. When the above composition is released, i.e., dispensed, from apressurized container, a quick-breaking temperature sensitive foam isformed.

The maximum amount of propellant used is often determined by itsmiscibility with other components in the composition to form a mixture,such as a homogeneous mixture. The minimal level of propellant used inthe composition is often determined by the desired foam characteristics,and its ability to substantially or completely evacuate the container.

The quick-breaking foaming agent comprises water and a surfactant, or acombination of surfactants, and an optional component(s), such as aC₁-C₆ alcohol, a C₁₄-C₂₂ alcohol, and combinations thereof. In someembodiments, the quick-breaking foaming agent can also comprise anemollient, which can also act as a humectant.

Suitable emollients include, but are not limited to, polyols. Preferredpolyols include propylene glycol and glycerol. The amount of emollientused in the quick-breaking foaming agent varies from about 0% to about20% w/w, preferably from about 0% to about 10% w/w, and more preferablyfrom about 2% to about 7.5% w/w.

In one embodiment, the quick-breaking foaming agent comprises a C₁-C₆alcohol and water. In a preferred embodiment, the quick-breaking foamingagent comprises a C₁-C₆ alcohol, a C₁₄-C₂₂ alcohol, water, and asurfactant. In an alternative embodiment, the quick-breaking foamingagent does not contain a C₁-C₆ alcohol.

In addition, the quick-breaking foaming agent can also comprise a pHadjusting agent. In one particular embodiment, the pH adjusting agent isa base. Suitable pH adjusting bases include bicarbonates, carbonates,and hydroxides such as alkali or alkaline earth metal hydroxide as wellas transition metal hydroxides. Preferably, the pH adjusting agent ispotassium hydroxide. Alternatively, the pH adjusting agent can also bean acid, an acid salt, or mixtures thereof. Further, the pH adjustingagent can also be a buffer. Suitable buffers include citrate/citric acidbuffers, acetate/acetic acid buffers, phosphate/phosphoric acid buffers,formate/formic acid buffers, propionate/propionic acid buffers,lactate/lactic acid buffers, carbonate/carbonic acid buffers,ammonium/ammonia buffers, and the like. The pH adjusting agent ispresent in an amount sufficient to adjust the pH of the composition tobetween about pH 4.0 to about 9.0, preferably about pH 4.0 to about 6.5.

Preferably, the quick-breaking foaming agent composition comprises aC₁-C₆ alcohol, more preferably a C₁-C₄ alcohol, such as methanol,ethanol, propanol e.g., isopropanol, butanol, and a mixture of two ormore thereof. A particularly preferred C₁-C₆ alcohol is ethanol or amixture of ethanol with and at least one other alcohol. The amount ofC₁-C₆ alcohol used in the quick-breaking foaming agent varies from about0% to about 95% w/w, preferably from about 55% to about 65% w/w, andmore preferably from about 58% to about 60% w/w.

The amount of C₁₄-C₂₂ alcohol in the quick-breaking foaming agent variesfrom about 0% to about 10% w/w, preferably from about 1% to about 5.0%w/w. In certain aspects, the quick-breaking foaming agent preferablycomprises from about 1% to about 2.5% w/w of the C₁₄-C₂₂ alcohol. Anespecially preferred amount of C₁₄-C₂₂ alcohol in the quick-breakingfoaming agent is from about 1.5% to about 2% w/w.

A preferred C₁₄-C₂₂ alcohol in the quick-breaking foaming agent is aC₁₆-C₂₀ alcohol. In particular, cetyl alcohol, stearyl alcohol, or amixture thereof is particularly preferred. Especially preferred is amixture of cetyl alcohol and stearyl alcohol. The ratio of cetyl alcoholto stearyl alcohol can range from about 60:40 to about 80:20, with theratio of about 70:30 being a preferred mixture ratio.

A wide variety of surfactants are useful in compositions of the presentinvention including, for example, ethoxylated non-ionic and ethoxylatedionic surfactants. Suitable surfactants for use in compositions of thepresent invention include, but are not limited to, fatty acidethoxylates, fatty alcohol ethoxylates, polysorbates, glycerol esterethoxylates, and block copolymers such as poloxamers. Examples of theseinclude Polysorbate 20, Polysorbate 60, Polysorbate 80, Laureth-4,Laureth-23, POE(15) glycerol monolaurate, and the like. In aparticularly preferred embodiment, the surfactant is Polysorbate 60,Laureth-4, POE(15) glycerol monolaurate, or mixtures thereof. The amountof surfactant present in the quick-breaking foaming agent generallyranges from about 0% to about 10% w/w, preferably from about 0.1% toabout 10% w/w, more preferably from about 0.1% to about 6% w/w, withfrom about 0.5% to about 5% w/w and from about 0.3% to about 0.5% w/wbeing especially preferred amounts.

Water, and optionally, a pH adjusting agent, generally comprises theremaining portion of the quick-breaking foaming agent. The amount ofwater present in the quick-breaking foaming agent ranges from about 10%to about 95% w/w, preferably from about 10% to about 90% w/w, morepreferably from about 20% to about 90% w/w, with from about 30% to about40% w/w, or alternatively from about 80% to about 95% w/w, beingespecially preferred.

While a typical amount of each component of the quick-breaking foamingagent is provided above, it should be appreciated that a particularamount of each component of the quick-breaking foaming agent depends onthe foam characteristics desired. Therefore, the scope of the presentinvention is not limited to those values provided herein.

In certain aspects, the quick-breaking temperature sensitive foam isformulated such that the foam breaking temperature is at or near skintemperature. The foam breaking temperature can be modulated by changingthe ratio of various components of the quick-breaking foaming agent,e.g., the C₁-C₆ alcohol to water ratio. In one particular embodiment,the foam breaking temperature can be adjusted to be from about 30° C. toabout 36° C., such as 30° C., 31° C., 32° C., 33° C., 34° C., 35° C.,and 36° C. For example, a particularly preferred foam breakingtemperature for clindamycin foam is 35° C.

Preferably, the pressurized container is a one-piece aluminum containerin which the inner surface is lined with a chemically inert lining. Apreferred inner surface lining is polyamide-imide (PAM) lacquer,supplied by HOBA Lacke and Farben GmbH. Typically, the container isfitted with an upright or inverted valve and a conventional foam spoutactuator.

In addition, the present invention provides various aspects related tosuch compositions, including: methods for modulating a foamcharacteristic; methods for improving the shelf-life of apharmaceutically active compound or its pharmaceutically acceptable saltor a prodrug thereof; methods for percutaneous treatment of variousdiseases, infections, and illnesses; and methods for evaluating foamcharacteristics.

III. Antibiotic Formulation

In one embodiment, the at least one pharmaceutically active compound isan antibacterial agent. Suitable antibacterial agents include, but arenot limited to, clindamycin, erythromycin, tetracycline, minocycline,doxycycline, penicillin, ampicillin, carbenicillin, methicillin,cephalosporins, vancomycin, and bacitracin, streptomycin, gentamycin,chloramphenicol, fusidic acid, ciprofloxin and other quinolones,sulfonamides, trimethoprim, dapsone, isoniazid, teicoplanin, avoparcin,synercid, virginiamycin, cefotaxime, ceftriaxone, piperacillin,ticarcillin, cefepime, cefpirome, rifampicin, pyrazinamide,ciprofloxacin, levofloxacin, enrofloxacin, amikacin, netilmycin,imipenem, meropenem, inezolid, pharmaceutically acceptable saltsthereof, and prodrugs thereof. Preferably, the antibacterial agent isclindamycin, or a pharmaceutically acceptable salt or a prodrug thereof.

Clindamycin is an antibiotic also known as methyl7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-2-pynolidinecarboxamido)-1-thio-L-threo-α-D-galacto-octo-pyranosideor methyl7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]amino]-1-thio-L-threo-α-D-galacto-octo-pyranoside.As used herein, the term “clindamycin” alone includes free-baseclindamycin as well as the pharmaceutically acceptable salts and estersthereof. Examples of pharmaceutically acceptable salts and esters ofclindamycin include, but are not limited to, clindamycin hydrochloride,clindamycin phosphate, clindamycin palmitate, and clindamycin palmitatehydrochloride. It is preferred to use a clindamycin salt or ester in thecompositions of the present invention, with clindamycin phosphate beingespecially preferred.

Suitable concentration ranges of the at least one pharmaceuticallyactive compound include, for example, from about 0.001% to about 50%w/w, preferably from about 0.01% to about 20% w/w, such as up to 15%w/w, and more preferably from about 0.1% to about 2% w/w. About 1% w/wis especially preferred.

The uses, properties, and methods of synthesis of clindamycin are setforth in U.S. Pat. No. 3,969,516, Stoughton, issued Jul. 13, 1976; U.S.Pat. No. 3,475,407, Bierkenmeyer, issued in 1969; U.S. Pat. No.3,487,068, issued in 1969; U.S. Pat. Nos. 3,509,127 and 3,544,551, Kaganand Magerlein, issued in 1970; U.S. Pat. No. 3,513,155, Bierkemeyer andKagan, issued in 1970; Morozowich and Sinkula, U.S. Pat. No. 3,580,904,issued in 1971 and U.S. Pat. No. 3,655,885, issued in 1972; U.S. Pat.No. 3,714,141, issued in 1973; U.S. Pat. No. 4,568,741, issued in 1986;and U.S. Pat. No. 4,710,565, issued in 1984. All of the foregoingpatents are incorporated herein by reference.

Additional knowledge in the art concerning clindamycin is found in, forexample, Magerlein, et al., Antimicro. Ag. Chemother. 727 (1966);Birkenmeyer and Kagan, J. Med. Chem., 13, 616 (1970); Oesterling, J.Pharm Sci. 59, 63 (1970); McGehee, et al., Am. J. Med. Sci. 256, 279(1968); D. A. Leigh, J. Antimicrob. Chemother. 7 (Supplement A), 3(1981); J E Gray et al., Toxicol. Appl. Pharmacol. 21, 516 (1972), and LW Brown and W F Beyer in Analytical Profiles of Drug Substances, Vol.10, K. Florey, editor (Academic Press, New York, 1981), pages 75-91.

It will be particularly apparent to those of skill in the art that thedevelopment of a clindamycin foam composition is especially surprising.First of all, clindamycin, such as clindamycin phosphate, is a watersoluble pharmaceutical agent. In order to make the foam composition aquick-breaking foam composition, the melting point of the compositionneeded to be within the temperature ranges already set forth (e.g., ator near skin temperature). In certain instances, the melting pointneeded to be adjusted and raised, which was difficult due to the watersolubility of clindamycin and the high concentrations of clindamycinused. These difficulties were overcome in part by adjusting the C₁-C₆alcohol to water ratios, such as the ethanol to water ratio.

Moreover, high concentrations of active compounds can also impact foamstructure and foam quality, as well as cause unwanted crystallization.Water-soluble active compounds can, in effect, remove water from thesystem, virtually changing the ratio of water to C₁-C₆ alcohol, andtherefore the foam characteristics, including the melting point. Thismay require intervention to achieve an acceptable foam quality. TheC₁-C₆ alcohol may not be a good solvent for water-soluble activecompounds, allowing crystallization at lower temperatures. Simplyincreasing the water content to prevent crystallization will alter thefoam characteristics and will change the solubility of the fattyalcohols, possibly causing them to precipitate. Crystallization can leadto loss of pharmaceutically active compounds and/or blockage of theaerosol valve.

Addition of a buffer is often used to improve the stability of an activecompound, and, in the case of aerosol containers, to reduce corrosion ofthe metal. In certain instances, the buffer can make the formulationless stable rather than more stable. In these cases, e.g., forclindamycin phosphate compositions, a pH adjustment rather than fullbuffering may be more effective. This is shown in FIG. 3, where higherlevels of buffer cause more degradation rather than less degradation.

In certain preferred embodiments, clindamycin phosphate is the activeagent and the quick-breaking foaming agent comprises a mixture of cetylalcohol and stearyl alcohol, which are dissolved in a water/ethanolsolution. Preferably, this composition is packaged in apolyamide-imide-lined aluminum can and pressurized with a propane/butanemixture as the propellant. Under the packaged pressure, the hydrocarbonpropellant liquefies and becomes miscible with the water/ethanolsolution. This liquefied hydrocarbon/water/ethanol solution allowsincreased solubility of the cetyl and stearyl alcohols compared towater/ethanol solutions alone. At temperatures above 11° C., thecontents of the can under pressure remain as a clear homogeneoussolution. Without being bound by any particular theory, it is believedthat the foam structure, i.e., characteristic, which is formed when thecomposition is released from the can is controlled by the solubility ofthe fatty alcohols (e.g., a mixture of cetyl alcohol and stearylalcohol) in the aqueous/ethanolic solution. Upon dispensing, thepropellant expands and vaporizes, allowing the fatty alcohols (e.g., amixture of cetyl alcohol and stearyl alcohol) to form a stable foamstructure. Thus, the ratios and choice of these components (e.g.,water:ethanol:cetyl alcohol:stearyl alcohol) affect the physicalcharacteristics of the foam.

Preferably, the water, ethanol, and propellant levels are selected toprovide the minimum solubility of the fatty alcohols in the can. Incertain aspects, the present inventors have discovered that a change inthe water:ethanol ratio alters foam characteristics. For example, anincrease in the water:ethanol ratio leads to a decrease in solubility ofthe fatty alcohols and an ensuing solidification of the foam structure.Conversely, a decrease in the water:ethanol ratio leads to an increasein solubility of the fatty alcohols and results in the formation of amore fluid foam.

Polysorbate is used as the preferred surfactant, with Polysorbate 60being an especially preferred surfactant. Without being bound by anytheory, in addition to its role in foam formation, it is believed thatPolysorbate 60 enhances cetyl alcohol and/or stearyl alcohol solubility.

The topical delivery composition of clindamycin phosphate is typicallyaccomplished by first dissolving the components into either water orethanol. Due to their limited solubility in water, cetyl alcohol andstearyl alcohol are dissolved in the ethanolic phase. Polysorbate 60 andpropylene glycol (i.e., an emollient which also can act as a humectant)are soluble in both ethanol and water, but for convenience are dissolvedin the ethanolic phase. Clindamycin phosphate and potassium hydroxide(i.e., a pH adjusting agent) are dissolved in water. The aqueous andethanolic phases are then added at the appropriate ratio into theindividual cans during the filling operation. The valves are fitted tothe cans and crimped into place. A metered amount of propellant is theninjected through the valve to complete the formulation. Another means offilling the cans involves a single-liquid-phase fill, in which thecomposition is kept warm to ensure homogeneity, followed by crimping andpropellant injection. Yet another means involves formulating the entirecomposition, including the propellant, in bulk, under pressure, and theninjecting the formulation into the crimped aerosol can.

A typical topical delivery clindamycin phosphate composition of thepresent invention, excluding the amount of propellant, is shown in Table1 below.

TABLE 1 A representative topical delivery clindamycin phosphatecomposition of the present invention. Component Amount (% w/w)Clindamycin phosphate, USP (calculated as 1.25 clindamycin) DehydratedAlcohol (Ethanol), USP 58.21 Cetyl Alcohol, NF 1.16 Stearyl Alcohol, NF0.53 Polysorbate 60, NF 0.42 Propylene Glycol, USP 2.11 Purified Water,USP 36.21 Potassium Hydroxide, USP, 10% w/w soln. 0.11The amount of clindamycin phosphate is based on its purity (typically800 mg/g calculated as clindamycin), and is adjusted to provide 1.00%calculated as clindamycin in the final composition, as shown in Table 1.Thus, the exact amount of clindamycin phosphate can vary depending onits purity.

In a preferred aspect, the amount of propellant added to the topicaldelivery clindamycin phosphate composition is about 2.8 g ofpropane/butane propellant for each about 50 g of the above mixture. Inaddition to its function as a propellant and for creating themicrostructure of the foam upon dispensing, the hydrocarbon or mixturesthereof helps to dissolve the cetyl alcohol and stearyl alcohol in theaqueous/ethanolic system to produce a clear, one-phase (i.e.,homogeneous) system in the container. Typically, the range of propellantconcentration is from about 2% to about 7% w/w relative to the totalamount of composition, preferably from about 3% to about 6% w/w, andmore preferably in the range of from about 4.6% to about 5.4% w/w.

While chlorofluorocarbons (CFCs) can also be used as propellants, due toenvironmental concerns the preferred propellants are hydrocarbons, inparticular, propane, butane, or a mixture thereof. Other suitablepropellants include dimethyl ether and hydrofluorocarbons such as 134aand 227. An especially preferred propellant is a mixture of propane andbutane.

Table 2 below summarizes some of the functions of each component in theclindamycin phosphate compositions of the present invention.

TABLE 2 Some of the functions of ingredients in clindamycin phosphatecompositions of the present invention. Component Purpose Clindamycinphosphate Active ingredient; topical anti-microbial Cetyl Alcohol, NFMaintains foam characteristics Stearyl Alcohol, NF Maintains foamcharacteristics Polysorbate 60, NF Enhances solubility of cetyl alcoholand stearyl alcohol and enhances foam formation. Dehydrated AlcoholSolvent for the active ingredient, and for (Ethanol), USP cetyl alcoholand stearyl alcohol Purified Water, USP Solvent, Moisturizer PropyleneGlycol, USP Humectant Potassium Hydroxide, pH control USP Propane/ButaneDissolves cetyl alcohol and stearyl Propellant alcohol in theaqueous/ethanolic (70 psig) system to produce a clear, one-phase system,propels the product from the can, and creates the microstructure of thefoam upon dispensing

Typically, the pressurized container is fitted with a dip tube; hence,the composition is dispensed by holding the can upright and depressingthe actuator button. The dispensed foam is thermolabile, i.e., aquick-breaking temperature sensitive foam. Preferably, the foamstructure collapses at, i.e., the foam breaking temperature is,approximately skin temperature, preferably between about 30° C. to about36° C., with the foam breaking temperature of about 35° C. beingespecially preferred. This allows the dispensing of a relatively stifffoam at ambient temperature and the subsequent breakdown of the foamstructure upon contact with the skin. Thus, the clindamycin phosphatequick-breaking temperature sensitive foam (i.e., clindamycin phosphatefoam) of the present invention can be directly applied to easilytargeted areas.

For less accessible areas, the clindamycin phosphate foam is generallydispensed onto a convenient surface prior to topical application. Thethermolabile nature of the clindamycin phosphate foam requires thedispensing of the composition onto a saucer, the cap of the can, orother cool surface so as to maintain the integrity of the foamstructure. The clindamycin phosphate foam can then be applied with ahand or an applicator.

The thermolabile qualities of the dispensed foam vehicle as a functionof temperature are shown in FIG. 1, which shows a critical temperature,i.e., foam breaking temperature, of about 35° C. Below this temperature,the foam remains quite stable and retains structural integrity for over5 minutes. Above 35° C., the cetyl and stearyl alcohol redissolve andthe foam breaks down.

The quality of the clindamycin phosphate foam is also affected by theambient temperature. For example, containers stored at highertemperatures (i.e., between 28° C. and 34° C.) dispense a softerclindamycin phosphate foam than those dispensed at lower temperatures(i.e., below 25° C.). A general description of clindamycin phosphatefoam quality as a function of container temperature is shown in Table 3below.

TABLE 3 Container Temperature and its Effect on Clindamycin PhosphateFoam Quality. Temperature Foam Quality Description Ambient Crisp, dry,well maintained shape. Foam has very fine temperatures bubbles. A smallscoop taken from the foam creates a below 25° C. hole with well definededges. Foam does not slide when surface is tilted. 31° C. Soft, slightlyflowing. Foam has fine bubbles. A small scoop taken from the foamcreates a hole with softer, rounded edges. Foam does not slide whensurface is tilted. 34° C. Very soft, moderately flowing. Foam hasvisibly larger bubbles. A small scoop taken from foam creates a holethat slowly flows together. Foam slowly slides when surface is tilted.37° C. Runny, weak, flowing. Foam composed of relatively large bubbles.Scooping tends to disrupt the bubbles breaking the foam structure. Foamreadily slides when surface is tilted.

As shown in Table 3, a preferred clindamycin phosphate foam dispensingtemperature is between about 23° C. to about 27° C., such as 25° C. orbelow. However, the temperature effects on foam formation arereversible. Thus, cooling a warmed container that dispenses a softclindamycin phosphate foam to below 25° C. will dispense an acceptablecrisp, dry foam.

The preferred propellant for use in the clindamycin phosphate foamcompositions of the present invention comprises a propane and butanemixture. A particularly preferred propellant comprises a mixture ofpropane, n-butane, and isobutane. A propellant composition comprisingabout 55% propane, about 30% n-butane, and about 15% isobutane isespecially preferred.

Without being bound to any particular theory, it is believed that upondispensing the composition from the container, the propellant in thesolution evaporates or vaporizes and creates the bubbles of the foamstructure. Some of this vaporized propellant is quickly released anddispersed to the atmosphere while the remainder is trapped within thefoam structure.

IV. Foam Characteristics Modification

Another aspect of the present invention provides a method for modulatinga foam characteristic of a quick-breaking temperature sensitive foamcomposition by changing the C₁-C₆ alcohol to water ratio in thequick-breaking foaming agent. In this manner, a variety of foamcharacteristics can be modified, including, but not limited to, clarity,density, viscosity, foam bubble size, foam expansion rate, foam flowrate, and/or foam breaking temperature.

In one embodiment, the C₁-C₆ alcohol to water ratio ranges from about1.5:1 to about 1.8:1, preferably from about 1.55:1 to about 1.75:1, andmore preferably from about 1.6:1 to about 1.7:1. In another embodiment,the C₁-C₆ alcohol to water ratio is less than about 1:7. In yet anotherembodiment, the C₁-C₆ alcohol to water ratio ranges from about 1:7 toabout 1:16, and is preferably about 1:7 or about 1:16.

In a further embodiment, the C₁-C₆ alcohol to water ratio in thequick-breaking foaming agent is modified to achieve a desired foambreaking temperature. Table 4 below shows the effect of the ethanol towater ratio on the melting point (i.e., foam breaking temperature) ofclindamycin phosphate foam. As shown in Table 4, a foam breakingtemperature of 35° C. is achieved by adjusting the ratio of ethanol towater to 1.60:1. This formulation was used in determining thethermolabile quality as shown in FIG. 1.

TABLE 4 Foam Breaking Temperature vs. Ethanol to Water Ratio.Ethanol:Water ratio 1.66:1 1.64:1 1.62:1 1.60:1 1.58:1 Melting Point (°C.) 32 33 34 35 36

V. Utility

Clindamycin phosphate foam compositions of the present invention areuseful in treating various bacteria-mediated diseases or illnesses viatopical application, e.g., in treating acne vulgaris and bacterialvaginosis. Analogously, other antibacterial agents or theircorresponding prodrugs can be used instead of clindamycin to treat otherbacteria-mediated diseases or illnesses. Suitable additionalantibacterial agents include, but are not limited to, erythromycin,tetracycline, minocycline, doxycycline, pharmaceutically acceptablesalts thereof, and prodrugs thereof. Furthermore, antifungal agents suchas ketoconazole can be used to treat fungal infections such as athlete'sfoot and the like.

It should be appreciated that when another pharmaceutical compound isused instead of clindamycin phosphate, one or more components of thecomposition (e.g., the quick-breaking foaming agent and/or thepropellant) can be modified or its amount adjusted to achieve a desiredfoam characteristic (e.g., smoothness of the foam, the foam breakingtemperature, stability of the active compound, and the like).

VI. Foam Evaluation

In another aspect, the present invention provides a method forevaluating foam characteristics. Such a method generally involvesproviding a visual aid that depicts various foam structures orcharacteristics, dispensing the foam, and evaluating the foam structureusing the visual aid (e.g., look-up table). Exemplary characteristicsthat can be depicted in the visual aid include shape, structure,clarity, density, viscosity, foam bubble size, foam expansion rate, foamflow rate, and foam breaking temperature. One or more of thesecharacteristics can be depicted in a visual aid such as a look-up table.

The visual aid (e.g., look-up table) can comprise one or more methodsthat describe the foam structure or characteristics, such as a visualdepiction (e.g., pictures either in a hard copy form or a digital, i.e.,electronic form) of various foam structures, numeric and/or alphanumericvalues for each foam structure (e.g., look-up values) and/or a literaldescription of each foam structure. The visual aid is typically preparedby generating different foam structures at various amounts of one ormore components of the quick-breaking temperature sensitive foamcomposition. An exemplary visual aid is shown in FIG. 2, which providesvarious formats, i.e., visual, numeric, and literal, for evaluating thefoam characteristics. These look-up tables and visual aids areespecially useful for research and development, good manufacturingpractice (GMP) and quality control (QC) methods.

In one embodiment, the foam to be evaluated is a quick-breakingtemperature sensitive foam composition, which is dispensed from apressurized container comprising a quick-breaking foaming agent and apropellant. The foam composition can also comprise a pharmaceuticallyactive compound or its pharmaceutically acceptable salt or a prodrugthereof.

Additional objects, advantages, and novel features of this inventionwill become apparent to those skilled in the art upon examination of thefollowing examples thereof, which are not intended to be limiting.

VII. Examples

The following examples are offered to illustrate, but not to limit, theclaimed invention.

Example 1

This example illustrates the effect of pH on the stability ofclindamycin phosphate using a citrate buffer solution and anepoxy-phenolic lined container.

Clindamycin phosphate foam composition samples similar to Table 1 wereprepared in aluminum aerosol cans with a standard epoxy-phenolic (epon)lining and fitted with a valve from the Precision Valve Company. In thisstudy, a citrate buffer solution was used to adjust the pH of themixture to pH 4.5, pH 5.5, and pH 6.5 using four different bufferconcentrations (i.e., 0, 0.1, 0.3, 0.5%) and two alternative emollientsor humectants, i.e., propylene glycol and glycerin. The containers werestored at 50° C. for 1 month and then examined. The results are shown inFIG. 3.

As shown in FIG. 3, higher buffer levels (e.g., 0.5%, 0.3%) result in ahigher amount of clindamycin phosphate degradation than lower bufferlevels (e.g., 0.1%, 0.0%). Moreover, clindamycin phosphate is morestable at a lower pH level.

Example 2

This example illustrates the effect of pH on the stability ofclindamycin phosphate using different inner-lining materials in thecontainer. Generally, the procedure of Example 1 was followed except asindicated below.

Low buffer levels at a pH of 4.5 or 6.5, including unbuffered pH 4.5,were tested in cans with either epoxy-phenolic, polyamide-imide (PAM),or Micoflex linings. Some of the PAM-lined cans were scratchedinternally to check for corrosion on bare aluminum. Cans were stored at4° C., 40° C., and 50° C. for 4 weeks and then examined. The results areshown in FIG. 4.

As shown in FIG. 4, the presence of a buffer solution is not necessaryto the stability of clindamycin phosphate. In addition, the PAM-linedcontainer afforded unexpectedly high clindamycin phosphate stability.Moreover, intentionally internally scratched containers resulted ineventual leakage of can contents. Thus, the integrity of the containerlining is important in maintaining the stability of clindamycinphosphate.

In general, a relatively severe degradation of clindamycin phosphate wasobserved at 50° C., and a moderate degradation of clindamycin phosphatewas observed at 40° C. However, since clindamycin phosphate is unstableat 50° C. (data not shown), tests at this temperature cannot be used topredict its stability at ambient temperature. As expected, in general,degradation of clindamycin phosphate is more rapid at highertemperatures.

Example 3

This example illustrates the effect of pH on the stability ofclindamycin phosphate using potassium hydroxide as a pH adjusting agent.Generally, the procedure of Example 1 was followed except as indicatedbelow.

Two pH levels of the clindamycin phosphate foam composition were tested:an unadjusted “natural” pH of 4.5; and an adjusted pH of 5.5 usingpotassium hydroxide. Cans tested were lined with PAM or Micoflexlinings. PAM-lined cans that were scratched internally were also tested.Samples were stored at 4° C., 25° C., 40° C., and 50° C. for up to 12months.

This testing led to the selection of the formulation shown in Table 1above, with a target pH of 5.0 (pH of formulated base at 40° C.). ThispH is adjusted with potassium hydroxide. PAM was confirmed as apreferred container lining for clindamycin phosphate foam compositions.

Further testing revealed that about 0.11% of a 10% potassium hydroxidesolution, as shown in Table 1, was needed to achieve a pH of about 5.

Example 4

This example shows the stability of clindamycin phosphate under variousconditions.

At each time/temperature point for the above stability experiments(i.e., Examples 1, 2, and 3), the following parameters were alsomeasured: weight loss, spray rate, pressure, pH (pH of degassed base at40° C.), potency (clindamycin phosphate concentration by HPLC),appearance upon dispensing and melting, and can lining and valveinteractions.

Negligible changes in spray rate, pressure, or appearance upondispensing and melting were observed over the course of the study eitherbetween temperatures or over time. Can lining interactions were observedin the early studies on epoxy-phenolic linings only; no valveinteractions were observed.

The results of the weight loss, pH, and potency tests for this stabilitytrial are shown in FIG. 5. As shown in FIG. 5, there is a minimal changein the concentration of clindamycin phosphate for pH 4.5 and pH 5.5 at25° C. over 6 months, whereas at 40° C. a decrease of almost 10% wasobserved. The degradation of clindamycin phosphate in Cleocin T showed asimilar pattern. Overall, this data indicated good stability of theclindamycin phosphate at normal storage temperatures. The majordegradant was clindamycin base.

Both formulations, pH 4.5 (natural pH) and pH 5.5 (adjusted pH), showeda slight weight loss at 4° C. and 25° C., but increased rates of weightloss as the temperature was increased. After three months of storage,losses of approximately 0.10 g, 0.25 g, and 0.45 g were recorded at 25°C., 40° C., and 50° C., respectively.

Example 5

This example illustrates the stability of clindamycin phosphate in theclindamycin phosphate foam compositions of the present invention.

Clindamycin phosphate foam compositions similar to that shown in Table 1above were stored at 25° C. and 40° C. Each foam composition wasanalyzed each month for appearance (e.g., foam characteristics such ascolor), pH, and the relative amount of clindamycin phosphate, which wasanalyzed using HPLC. The stability test results at various timeintervals, i.e., at 0-9 months, are shown in Table 5.

TABLE 5 Stability Test Results of 1% Clindamycin Phosphate Foam.Container: 35 × 125 mm aluminum can Closure: 1″ Aluminum cup dip tubeTotal Related Prod. & Clindamycin Clindamycin Substances AppearanceApparent pH Pack. Inter. (% w/w) (% w/w) (% peak area) MethodsSpecifications Storage Month See A Report See B 0.90-1.10 ≦0.10 Report25° C./ 0 Pass 5.0 Pass 0.97 0.004 1.23 50% 1 Pass 5.0 Pass 1.03 0.0040.89 RH 2 Pass 5.3 Pass 1.02 0.006 1.26 3 Pass 5.0 Pass 1.01 0.008 0.456 Pass 4.9 Pass 1.00 0.009 1.37 9 Pass 5.4 Pass 1.01 0.013 0.54 40° C./0 Pass 5.0 Pass 0.97 0.004 1.23 75% 1 Pass 5.0 Pass 1.02 0.013 1.06 RH 2Pass 5.3 Pass 1.04 0.025 0.79 3 Pass 4.9 Pass 1.01 0.032 0.37 6 Pass 4.8Pass 0.99 0.062 1.92 9 Pass 5.2 Pass 0.99 0.097 0.76 A = Upon actuation,a white foam is produced. At 40° C., the product is a clear, colorlessto pale yellow solution with no visible foreign matter. B = No visibleevidence of product interaction with can, lining, or valve.

Example 6

This example illustrates a clinical trial for evaluating theeffectiveness of the clindamycin phosphate foam of the presentinvention.

The clinical trial was conducted at multiple centers. A total of 125male and female subjects, 12 years of age or older, with mild tomoderate acne vulgaris were selected for a randomized, double-blindedtest. Each subject received one of the three treatments: 1% clindamycinphosphate foam, vehicle foam (i.e., placebo), or 1% clindamycinphosphate topical gel. Subjects were randomized in a 2:1:2 ratio(clindamycin phosphate foam:placebo:clindamycin phosphate gel).

Subjects were assigned to a treatment group upon randomization. Subjectsand nurses/coordinators were un-blinded to the form of study medicationassigned (foam or gel). Assignment to the foam treatment group (activeor placebo) was blinded for subjects, nurses/coordinators, andinvestigators. The investigators/designee (i.e., person who has beentrained and assigned to perform efficacy evaluations) were blinded tothe form of study medication assigned (foam or gel) and subjects wereinstructed to not to discuss this information with theinvestigator/designee.

The study duration was 12 weeks with visits at baseline (week 0, day 1),week 3, week 6, week 9, and week 12. All treatments were administeredonce daily (morning or evening) for 12 weeks. Approximately fiftysubjects were randomly assigned to treatment with clindamycin phosphatefoam, approximately twenty five subjects were randomly assigned toplacebo, and approximately fifty subjects were randomly assigned toclindamycin phosphate gel. Subjects applied a sufficient amount of studymedication to cover the entire face. If the subject had neck, upperchest, and/or upper back acne, he or she was allowed to apply the studymedication to those areas as well. However, the neck, upper chest, andupper back areas were not included in the efficacy evaluation.

Efficacy of the study medication was evaluated based on lesion counts(total, inflammatory, and non-inflammatory) and an investigator's staticglobal assessment (5-point scale) at baseline and at weeks 3, 6, 9, and12. At week 12, an additional investigator's static global assessmentutilizing a 6-point scale was performed. In addition, a subject's globalassessment was made at baseline and at weeks 3, 6, 9, and 12. Theefficacy results are shown in Table 6 below and illustrate that theinventive foam has superior efficacy.

TABLE 6 Efficacy Study Results. Inventive Comparative Foam Gel PlaceboNumber of Subjects 49 46 24 Total Lesions (median) −46.2 −41.1 −32.8Inflammatory Lesions (median) −60.0 −54.4 −38.5 Non-inflammatory Lesions(median) −38.5 −25.0 −28.5

As the efficacy study results show, the clindamycin phosphate foamcomposition of the present invention is significantly more effectivethan the clindamycin gel composition that is currently available.

Example 7

This example illustrates a second clinical trial with more subjects forevaluating the effectiveness of the clindamycin phosphate foam of thepresent invention.

A 12-week, multi-center (18 sites), randomized, double-blind,double-dummy, vehicle-controlled study of 1026 male and female subjects,12 years of age or older, with mild to moderate acne vulgaris wasconducted. Subjects had an Investigator's Static Global Assessment(ISGA) of 2 or greater (see, Table 7), 17-40 facial inflammatory lesions(papules plus pustules) including nasal lesions, and 20-150 facialnon-inflammatory lesions (open and closed comedones) excluding nasallesions.

Subjects were in good general health. Excluded from participation werethose who had any active nodulo-cystic lesions or a history of regionalenteritis or inflammatory bowel disease. Subjects were also excludedfrom participation if they had used the following to treat their acne:systemic antibiotic or steroid therapy within the prior 4 weeks;systemic retinoids within the prior 3 months; or topical anti-acnemedications or topical antibiotics in the prior 4 weeks. Subjects werealso excluded if their estrogen or androgen use had changed within 12weeks or less, or if they intended to use any of the following types ofproducts or procedures concomitantly: benzoyl peroxide, salicylic acid,retinol, α- or β-hydroxy acids, neuromuscular blocking agents, tanningbooths, sunbathing, facial procedures (e.g., chemical or laser peels),or medications known to exacerbate acne.

Subjects were enrolled and randomized to receive one of four treatmentsin a 3:3:1:1 ratio: (1) 1% clindamycin phosphate foam; (2) 1%clindamycin phosphate gel; (3) vehicle foam; or (4) vehicle gel. Thestudy duration was 12 weeks with visits at Baseline and Weeks 3, 6, 9,and 12. All treatments were administered once daily (i.e., morning orevening) for 12 weeks.

Efficacy of each treatment was evaluated by performing acne lesioncounts (total, inflammatory, and non-inflammatory), an Investigator'sStatic Global Assessment of facial acne vulgaris, and a Subject's GlobalAssessment at each visit. Safety was assessed from vital signs, clinicallaboratory assessments, and reported adverse events. Additionally,evaluations of the severity of the signs (e.g., scaling, dryness,erythema, oiliness) and symptoms (e.g., burning, itching) of acnevulgaris were performed at all visits. The scale used for theInvestigator's Static Global Assessment of facial acne vulgaris is shownin Table 7 below. The efficacy results are shown in Table 8(Investigator's Static Global Assessment), Table 9 (percent reduction ininflammatory lesion counts), Table 10 (percent reduction innon-inflammatory lesion counts), and Table 11 (percent reduction intotal lesion counts) below.

TABLE 7 Investigator's Static Global Assessment Scale of Facial AcneVulgaris. Score Definition Grade 0 Normal, clear skin with no evidenceof acne vulgaris Grade 1 Skin almost clear: rare non-inflammatorylesions present, with rare non-inflamed papules (papules must beresolving and may be hyper-pigmented, though not pink-red) requiring nofurther treatment in the Investigator's opinion Grade 2 Somenon-inflammatory lesions are present, with few inflammatory lesions(papules/pustules only, no nodulo- cystic lesions) Grade 3Non-inflammatory lesions predominate, with multiple inflammatory lesionsevident: several to many comedones and papules/pustules, and there mayor may not be 1 small nodulo-cystic lesion Grade 4 Inflammatory lesionsare more apparent: many comedones and papules/pustules, and there may ormay not be a few nodulo-cystic lesions Grade 5 Highly inflammatorylesions predominate: variable number of comedones, many papules/pustulesand nodulo-cystic lesions

TABLE 8 Investigator's Static Global Assessment: Subjects with Successat Week 12. Clindamycin Vehicle Vehicle Foam Clindagel ™ Foam Gel Number386 385 127 128 of Subjects Success 120 (31%) 105 (27%) 23 (18%) 26(20%) Confidence −2.60%, 10.23% Limit¹ P-value² 0.0025 Note: Success isdefined as the proportion of subjects who have an Investigator's StaticGlobal Assessment score of 0 or 1 at Week 12 (or end of treatment).¹Two-sided 95% confidence interval for the difference in success ratebetween Clindamycin Foam and Clindagel ™. ²P-value is derived fromCochran-Mantel-Haenszel test (α = 0.05) stratified by site and comparesClindamycin Foam against Vehicle Foam. Breslow-Day Test for Homogeneityof the by-site Odds Ratios for Clindamycin Foam versus Clindagel ™Treatment Success: p = 0.9445, for Clindamycin Foam versus Vehicle Foamp = 0.6505

TABLE 9 Percent Reduction in Inflammatory Lesion Counts from Baseline toWeek 12. Clindamycin Vehicle Vehicle Foam Clindagel ™ Foam Gel Number of386 385 127 128 Subjects Percent Reduction from Baseline n 385 384 127128 mean (std) 49.0(37.1) 45.0(37.6) 34.7(37.5) 36.6(40.5) median 57.950.0 40.5 45.9 min, max (−93, 100) (−135, 100) (−112, 100) (−111, 96)confidence −0.97%, 9.17% limit¹ p-value² 0.1096 0.0001 0.0478 <.0001¹Two-sided 95% confidence interval for the difference in mean percentreduction between Clindamycin Foam and Clindagel ™. Treatment-by-siteinteraction: p = 0.7291. ²P-values are derived from a parametric ANOVAmodel (top) and a rank-transformed model (bottom) (α = 0.05) with termsfor treatment and site and compare Clindamycin Foam against Clindagel ™and Vehicle Foam, respectively.

TABLE 10 Percent Reduction in Non-Inflammatory Lesion Counts fromBaseline to Week 12. Clindamycin Vehicle Vehicle Foam Clindagel ™ FoamGel Number of 386 385 127 128 Subjects Percent Reduction from Baseline n386 384 127 128 mean (std) 38.3(31.7) 30.2(38.8) 27.1(38.4) 20.8(45.8)median 41.3 33.3 31.0 26.3 min, max (−82, 100) (−183, 100) (−192, 90)(−200, 100) confidence 3.25%, 13.03% limit¹ p-value² 0.0013 0.00180.0037 0.0038 ¹Two-sided 95% confidence interval for the difference inmean percent reduction between Clindamycin Foam and Clindagel ™.Treatment-by-site interaction: p = 0.6922. ²P-values are derived from aparametric ANOVA model (top) and a rank-transformed model (bottom) (α =0.05) with terms for treatment and site and compare Clindamycin Foamagainst Clindagel ™ and Vehicle Foam, respectively.

TABLE 11 Percent Reduction in Total Lesion Counts from Baseline to Week12. Clindamycin Vehicle Vehicle Foam Clindagel ™ Foam Gel Number of 386385 127 128 Subjects Percent Reduction from Baseline n 385 384 127 128mean (std) 42.8(27.5) 35.7(31.6) 30.5(29.6) 27.6(34.4) median 45.7 39.933.7 34.0 min, max (−43, 100) (−93, 100) (−87, 85) (−77, 91) confidence3.03%, 11.20% limit¹ p-value² 0.0007 <.0001 0.0014 <.0001 ¹Two-sided 95%confidence interval for the difference in mean percent reduction betweenClindamycin Foam and Clindagel ™. Treatment-by-site interaction: p =0.6782. ²P-values are derived from a parametric ANOVA model (top) and arank-transformed model (bottom) (α = 0.05) with terms for treatment andsite and compare Clindamycin Foam against Clindagel ™ and Vehicle Foam,respectively.

Of the 1026 subjects enrolled in the study, 54% were female and 46% weremale. The majority of the subjects were Caucasian (64%) and the averageage was 18.9 years (range from 12-55 years). There was an evendistribution of age in the study, with 50% (516/1026) in the 12-16 yearold age group and 50% (510/1026) in the age group of 17 years or older.Lesion counts (total, inflammatory and non-inflammatory) were similaracross all treatment groups at Baseline. Overall, the majority ofsubjects (54%; 549/1026) had an Investigator's Static Global Assessmentscore of 3 at Baseline, with similar distribution across the treatmentgroups. There were no significant differences in the demographic ordisease characteristics of the treatment groups at Baseline.

As the efficacy study results show (see, Tables 8-11), the clindamycinphosphate foam composition of the present invention is statisticallysuperior in clinical efficacy to 1% clindamycin phosphate gel based onmean percent reduction for all three lesion counts (total, inflammatory,and non-inflammatory) and is statistically superior to the vehicle foambased on mean percent reduction for all three lesion counts (total,inflammatory, and non-inflammatory) and treatment success based on theInvestigator's Static Global Assessment at the end of treatment.

The clindamycin phosphate foam composition of the present invention wasalso very well-tolerated. The most commonly reported dermal adverseevent was application site burning: 6% (24/386) of subjects in theClindamycin Foam group; 1% (3/385) of subjects in the Clindagel™ group;7% (9/127) of subjects in the Vehicle Foam group; and 2% (2/128) ofsubjects in the Vehicle Gel group. However, these events were mild ormoderate, intermittent in nature, and well-tolerated by the subjects inthe study. All other application site reactions reported withClindamycin Foam, including pruritus and dryness, occurred in <2% ofsubjects.

Example 8

This example shows a study on the comparative absorption of aclindamycin phosphate foam formulation versus a once-daily clindamycinphosphate topical gel formulation.

Methods: The pharmacokinetic absorption profile of a clindamycinphosphate 1% foam formulation (Clindamycin Foam) was compared to that ofa clindamycin phosphate 1% gel formulation (Clindamycin Gel). This studywas a single center, randomized, open-label study of male and femalesubjects, 12 years of age or older, with mild to moderate acne vulgaris.For each treatment, Clindamycin Foam or Clindamycin Gel was administeredonce a day in the morning for 5 days. Subjects applied 4 grams of studymedication to the face, neck, upper chest, and upper back at everytreatment application. Evaluation of absorption occurred on the fifthday of treatment and included plasma and urine determination ofclindamycin collected over a 12-hour period following application of thelast dose. Plasma samples were obtained predose (i.e., prior toinitiation of study drug treatment) on Day 1 of treatment and on Day 5within 30 minutes prior to treatment application and at 1, 2, 4, 8, and12 hours following treatment application. Urine was collected for 12hours at Day 5 for determination of excretion of clindamycin. Treatmenttolerability was assessed by reported adverse experiences.

Demographics: Twenty-four subjects were enrolled and randomized toreceive one of the two treatments (22 subjects were caucasian, 1 wasblack, and 1 was hispanic). The mean age of the subjects was 19 years(range: 13-46 years), the mean height was 66.9 inches (range: 62-71inches), and the mean weight was 146.1 pounds (range: 113-185 pounds).

Pharmacokinetic Results: Clindamycin concentrations were detectable in11 of the 12 subjects following Clindamycin Foam administration and inall 12 subjects following Clindamycin Gel administration. Overall, themean C_(max) and AUC₍₀₋₁₂₎ values were lower for Clindamycin Foamcompared to Clindamycin Gel, with a 25% lower mean C_(max) and a 9%lower AUC₍₀₋₁₂₎; the mean T_(max) values were similar between the 2treatments (see, Table 12 and FIG. 6). The fraction of clindamycin doseexcreted in urine was marginal following both treatments, at 0.24%following Clindamycin Foam application compared to 0.30% followingClindamycin Gel application.

TABLE 12 Pharmacokinetic Parameters for Clindamycin (Plasma ClindamycinConcentration) Clindamycin Foam Clindamycin Gel Arithmetic ArithmeticPharmacokinetic Parameters Mean SD Mean SD C_(max) (ng/mL) 1.562 0.8132.075 1.239 T_(max) (hr) 6.18 2.08 6.66 2.46 AUC₍₀₋₁₂₎ (ng-hr/mL) 13.696.248 15.12 10.26

Safety: Few adverse events were reported during the study, with only 4of 24 subjects reporting a total of four adverse events between the timesubjects initiated study treatment and completion of the study. Twosubjects assigned to treatment with Clindamycin Foam reported oneadverse event each (i.e., application site dryness and headache NOS) andtwo subjects assigned to Clindamycin Gel reported one adverse event each(i.e., blister and dizziness). Most adverse events were mild in severityand were considered to be unrelated to the study drug treatment; onlythe report of dryness at the application site was probably related tostudy drug treatment. There were no deaths, serious adverse experiences,episodes of diarrhea, or other significant adverse experiences reportedand no subjects discontinued the study prior to completion of all blooddraws on Day 5 (study termination).

Conclusions: The extent of clindamycin absorption following ClindamycinFoam administration was lower, but comparable to that followingClindamycin Gel administration. The mean C_(max) and mean AUC₍₀₋₁₂₎values in plasma on Day 5 were 25% and 9% lower, respectively, followingthe Clindamycin Foam treatment compared to Clindamycin Gel treatment.The amount of clindamycin excreted in urine during the first 12-hourspost-dose was 21% lower for the Clindamycin Foam treatment group.Clindamycin Foam administered topically for 5 consecutive days in 4 gramdoses appeared to be safe and well-tolerated by the subjects.

Example 9

This example shows a comparative study on the skin penetration ofvarious clindamycin phosphate formulations in vitro using a human skinmodel system.

Summary

The purpose of the study was: (1) to quantify the in vitro percutaneousabsorption of clindamycin; and (2) to characterize clindamycindistribution in different skin compartments, following the applicationof (1) a 1% clindamycin phosphate foam formulation of the presentinvention (Foam); (2) a 1% ClindaGel™ topical gel formulation (Gel); and(3) a 1% Cleocin T® solution formulation (Solution), in dermatomed humanskin using the finite dose technique and In-Line Diffusion Cells.

Methods: The formulations (Foam, Gel, and Solution) were tested forpercutaneous absorption of clindamycin on skin sections from threedifferent skin donors. The skin sections were dosed for 24 hours, duringwhich the dermal receptor solution was collected every 4 hours and savedfor subsequent analysis. At the end of the dosing period, the surface ofthe skin was washed and the skin was split into epidermis and dermis.The wash from the surface of the skin, the epidermis, the dermis, andsamples of the receptor fluid were then analyzed for clindamycin usinghigh performance liquid chromatography coupled with mass spectrometry(LC/MS).

Results: At the end of the 24-hour dosing period, the Solutionformulation contained the highest amount of clindamycin in the receptorfluid, followed by the Foam formulation and lastly the Gel formulation(see, Table 13, below). As shown in Table 13, there was no significantdifference (p>0.1) in the cumulative amount of clindamycin in thereceptor fluid from Foam and Solution formulations at 24 hours afterdosing. At that time point, both Foam and Solution formulationsdelivered more clindamycin into receptor fluid than the Gel formulation(p<0.1). Similar amounts of clindamycin were found in the epidermis fromall formulations. However, the Gel formulation resulted in a higheramount of clindamycin in the dermis than the Foam and Solutionformulations. Both the Foam and Solution formulations resulted insimilar amounts of clindamycin in the dermis.

TABLE 13 Clindamycin in Receptor Fluid and Skin at 24 Hours After Dosing(Mean ± Std. Error) Formulation Foam Gel Solution Distribution (n = 3 ×3) (n = 3 × 3) (n = 3 × 3) In Receptor Fluid 0.16% ± 0.02% 0.05% ± 0.04%0.39% ± 0.16% In Dermis 3.08% ± 0.71% 5.45% ± 1.33% 3.33% ± 0.83% InEpidermis 5.35% ± 0.69% 5.48% ± 1.25% 5.78% ± 1.54%The flux profiles of the three formulations were very similar in form,with the maximum rate achieved already in the first time point (i.e.,between 0 to 4 hours after application) and decreasing steadilythereafter. The highest maximum rate was produced from the Solutionformulation, followed by the Foam and lastly from the Gel formulation.

Conclusion: The Foam formulation delivered clindamycin with a profilesimilar to that of the Solution formulation, which produced the highestdelivery of clindamycin in the current in vitro skin permeation study.The amount of clindamycin in the epidermis, dermis, and receptor fluidwas very similar and exhibited no significant differences between theFoam and the Solution formulations.

Example 10 Introduction

The 1% clindamycin Foam formulation is suitable as a topical treatmentfor acne. In contrast to products currently available on the market, theFoam formulation provides for elegant, rapid, and non-staining drugdelivery, leaving very little residue on the skin. The current studyinvestigated and compared the delivery, skin permeation profile, anddrug distribution in the skin of clindamycin from Foam, Gel, andSolution formulations.

The in vitro human skin penetration model has proven to be a valuabletool for the study of percutaneous absorption and the determination ofthe pharmacokinetics of topically applied drugs. This method hashistoric precedent for accurately predicting in vivo percutaneousabsorption kinetics. The model uses excised human skin mounted inspecially designed diffusion chambers or cells that allow the skin to bemaintained at a temperature and humidity that match typical in vivoconditions. A finite dose (e.g., 4-6 mg/cm²) of the formulation isapplied to the outer surface of the skin and drug absorption is measuredby monitoring its rate of appearance in the receptor solution bathingthe inner surface of the skin. Skin content can be determined byextraction and analysis of the drug from different skin layers. As such,data defining total absorption, rate of absorption, and drugdistribution in the skin and on its surface can be accurately determinedusing this model.

Deviations

One cell (1G) did not pass the skin integrity test, and was used insteadas an untreated control. None of the other cells was excluded from theresults.

Test Articles

Analytical standards were obtained from Sigma Chemicals and UnitedStates Pharmacopeia (USP).

The tested formulations were as follows:

-   1. Foam: 1% clindamycin phosphate foam of the present invention;    Manufacturer's lot no. SEAX-C.-   2. Gel: 1% Clindagel™ topical gel (clindamycin phosphate topical gel    equivalent to 1% clindamycin; Galderma Laboratories, L.P., Fort    Worth, Tex.); Manufacturer's lot no. RFDA.-   3. Solution: 1% Cleocin T® Solution (clindamycin phosphate topical    solution, USP; equivalent to 1% (10 mg/mL) clindamycin; Pharmacia &    Upjohn Company, Kalamazoo, Mich.); Manufacturer's lot no. 89FTK.

Methods and Procedures

Methodology: Percutaneous absorption was measured using the in vitroskin finite dose technique. Human abdomen skin without obvious signs ofskin disease, obtained from cosmetical surgery, was used in this study.The skin samples were dermatomed to approximately 0.25 mm, sealed in awater-impermeable container, and stored at ˜−80° C. until the day of theexperiment. Prior to use, the skin samples were thawed by exposing thecontainer to ambient temperature.

Skin from a single donor was cut into multiple smaller sections, butremained large enough to fit on an 0.64 cm² exposure area of In-Linediffusion cells (Permegear Inc., Bethlehem, Pa.). The dermal chamber wasfilled to capacity with a receptor solution of 10-times dilutedphosphate-buffered isotonic saline (PBS), pH 7.4±0.2, and the epidermalchamber was left open to the ambient laboratory environment. The cellswere then placed in a cell warmer support in which the temperature ofthe dermal chamber was maintained at 37° C.±0.2° C.

To assure the integrity of each skin section, its permeability totritiated water was determined before application of the testformulations (Franz et al., Abst. J. Invest. Derm., 94:525 (1990)).Following a brief (0.5-1 hour) equilibrium period, 100 μL of ³H₂O(Moravek, Calif., sp. Act. ˜5 μCi/mL) was layered across the top of theskin using a pipette so that the entire exposed surface was covered.After 5 minutes, the ³H₂O aqueous layer was removed. At 30 minutes, thereceptor solution was collected and analyzed for radioactive content byliquid scintillation counting. Skin specimens in which penetration of³H₂O was less than 1.75% applied dose were considered acceptable.

Dosing and Sampling: The Foam formulation was first dispensed as foaminto a 20-mL vial and warmed to 37° C. in a water bath to thoroughlyliquefy the foam. All formulations were then applied to the skinsections using a positive displacement pipette set to deliver 5 μL. Eachtest formulation was applied to three replicate sections of the samedonor skin at a target dose of 5 μL/0.64 cm². The dose was spread overthe entire surface with the tip of the pipette. The skin sections weredosed for 24 hours, during which the dermal receptor solution wascollected every 4 hours and saved for analysis. A spare chamber was usedwith untreated skin to test for any interfering substances during theanalytical assay.

At the end of the 24-hour dosing period, following the last receptorsolution sample collection, the skin surface was washed by applying 50μL of acetonitrile, wiped with a pre-cut tissue paper twiceconsecutively, and stripped with a transparent tape twice consecutively.The tissue paper and tape were placed in a vial. The skin was placed ona 50° C. heat block for 1.5 minutes, then the epidermis was carefullypeeled off the skin and placed in one vial, while the remaining piece ofskin (dermis) was placed into another vial. To each of these threevials, 5 mL of acetonitrile was added to extract the drug from thesamples.

Preparation of Samples: Clindamycin was Extracted from the ReceptorSolutions by running 3.0 mL of the samples (with 200 μL addition of aninternal standard: lincomycin hydrochloride) through solid phaseextraction (C18 SPE cartridges) and eluting the clindamycin using 0.5 mLmethanol. After vortexing, 100 μL of solution was placed into HPLC vialscontaining 900 μL of Milli-Q purified water and mixed well beforeanalysis. From the acetonitrile based samples, 100 μL of solution wasmixed with 100 μL of internal standard solution in test tubes. After theaddition of 800 μL Milli-Q water, the tubes were centrifuged and thesupernatant was transferred into HPLC vials for analysis.

Analytical Methods: Quantification of clindamycin was performed by highperformance liquid chromatography combined with mass spectrometry(LC/MS/MS) on a Micromass LC/MS/MS system. The mobile phase consistingof acetonitrile, methanol, water, and formic acid (33%:33%:33%:0.1%) waspumped through a Keystone Aquasil C18 column (1.0×30 mm, 3μ) at ambienttemperature at a flow rate of 0.05 mL/min. (5 minute run duration).Forty microliters of sample were injected. Eluting peaks were monitoredat the M/Z of 425>126 Da. Peak areas were quantified to concentrationusing an external standard of clindamycin hydrochloride correlated to aninternal standard lincomycin hydrochloride.

Pivotal Study Details: This study was designed to assess the effects ofdifferent formulations on clindamycin percutaneous absorption. Threeskin donor samples, each cut into 9-10 replicate sections, were preparedand mounted onto chambers. Receptor solution samples were collected at4-hour time intervals, up to 24 hours post-application. The receptorsolution used throughout was PBS (i.e., 1 mM phosphate buffer solution,pH 7.4 at 25° C.; BioChemika). Extracts from the surface wash,epidermis, and dermis were analyzed to obtain the mass balance of theapplied drug. Data for the different formulations were compared andevaluated for statistical differences using a Student-t test formultiple comparisons.

Results

TABLE 14 Skin Integrity Test Results. Donor ID Sex Integrity TestResults* 2003.001 Female 0.05 ± 0.02 Pass** 2003.002 Female 0.04 ± 0.05Pass 2003.003 Female 0.03 ± 0.02 Pass *Results are reported as % applied³H₂O ± standard deviation; Acceptance: <1.75%. All skin samples wereobtained from abdominoplastic surgeries. Donor age is unknown.**Excluding 1 cell that failed the test.

Drug Content and Distribution: The results for the mean percutaneousabsorption of clindamycin in the tested formulations are summarizedgraphically in FIG. 7 as the cumulative penetrated amount (i.e., meantotal absorption) in 24 hours and in FIG. 8 as the flux profile for a24-hour period. The numerical data are presented in Table 15 below. FIG.9 shows the distribution of clindamycin in different skin layers.

TABLE 15 Clindamycin Distribution on Skin Surface, in Skin Layers, andin Receptor Fluid at 24 Hours After Dosing (Mean ± Standard Error). FoamGel Solution Distribution (n = 3 × 3) (n = 3 × 3) (n = 3 × 3) InReceptor Fluid 0.16% ± 0.02% 0.05% ± 0.04% 0.39% ± 0.16% In Dermis 3.08%± 0.71% 5.45% ± 1.33% 3.33% ± 0.83% In Epidermis 5.35% ± 0.69% 5.48% ±1.25% 5.78% ± 1.54% In Surface Wash 2.77% ± 0.39% 20.72% ± 1.59%  6.56%± 1.12% Total Recovery 11.37% 31.70% 16.06%

In FIG. 7, the cumulative amount of clindamycin that penetrated throughthe skin over 24 hours increased sharply for all formulations already inthe first time point, gradually reaching a plateau towards 24 hours. TheSolution formulation delivered the most clindamycin, followed by theFoam formulation, and lastly the Gel formulation. Both Solution and Foamformulations delivered significantly more clindamycin into the receptorfluid than the Gel formulation (p<0.06 and p<0.05, respectively) up tothe 24-hour time point. There was no significant difference (p>0.1) inthe cumulative amount of clindamycin in the receptor fluid up to 24hours from Foam and Solution formulations.

This can further be observed from the flux profile. The flux plots inFIG. 8 show that the maximum rate of delivery was achieved in the firsttime point (0 to 4 hours after application) for all formulations, anddecreased steadily thereafter. The flux profiles of the threeformulations were very similar in form. The highest maximum rate wasproduced from the Solution formulation, followed by the Foamformulation, and lastly from the Gel formulation.

Similar amounts of clindamycin were found in the epidermis for allformulations. Although the Gel formulation resulted in a higher amountof clindamycin in the dermis, both Foam and Solution formulationsresulted in similar amounts of clindamycin in the dermis.

The amount recovered from the wash was very low, due to the highaffinity of clindamycin to the adhesive material in the tape, which wasfiltered during sample preparation. The mass balance of the experimentsis also presented in Table 15.

Conclusions

Data from this study demonstrated that:

-   1. The Foam vehicle facilitates a higher level of clindamycin    delivery across the skin than the Gel formulation, but a lower level    than the Solution formulation;-   2. The maximum flux rate was achieved shortly after application of    all formulations, with the order of magnitude from highest to lowest    being: Solution>Foam>Gel; and-   3. The skin distribution at 24 hours showed an equal amount of    clindamycin in the epidermis for all formulations and a slightly    higher amount in the dermis for the Gel formulation compared to the    Foam and Solution formulations.    Thus, this study shows that the clindamycin phosphate foam    formulation of the present invention is superior to a clindamycin    gel formulation for enhanced delivery of clindamycin across the skin    at a higher flux rate. Further, unlike a clindamycin solution    formulation, the clindamycin phosphate foam formulation of the    present invention does not readily run off the site of application,    providing for the administration of a more controlled amount of    clindamycin.

Example 11

This example illustrates non-alcoholic and alcoholic foam compositionsof the present invention comprising a combination of clindamycinphosphate and tretinoin.

NON-ALCOHOLIC CLINDAMYCIN/TRETINOIN FOAM % w/w % w/w (without (with ITEMINGREDIENT propellant) propellant) 1 Purified water 86.90 82.545 2Propylene glycol 7.50 7.13 3 Disodium EDTA 0.10 0.10 4 Clindamycinphosphate 1.255 1.191 5 Laureth-4 2.00 1.90 6 POE (15) glycerylmonolaurate 2.00 1.90 7 Butylated hydroxytoluene 0.02 0.02 8 Retinoicacid (tretinoin) 0.025 0.024 9 Methyl paraben 0.20 0.19 10 Aerosol Base(Items 1-9) 100.00 95.00 11 Hydrocarbon propellant NIL 5.00 Total 100.00100.00

Items 1-4 are added stepwise to mixing vessel A. Items 5-9 are addedstepwise to mixing vessel B. Each phase is heated to approximately 60°C. While stirring, Phase B is added to Phase A, mixed until uniform, andcooled to 30° C. The Aerosol Base (Item 10) is then added to an aerosolcan, and a valve is secured onto the aerosol can. A propellant (Item 11)is added to the aerosol package (i.e., aerosol can with valve containingAerosol Base). The Aerosol Package is placed into a 55° C. water bathfor 1-2 minutes, then shaken well and cooled to room temperature. TheAerosol Package is shaken immediately prior to dispensing.

ALCOHOLIC CLINDAMYCIN/TRETINOIN FOAM % w/w % w/w (without (with ITEMINGREDIENT propellant) propellant) 1 Purified water 81.90 77.795 2Ethanol 5.00 4.75 3 Propylene glycol 7.50 7.13 4 Disodium EDTA 0.10 0.105 Clindamycin phosphate 1.255 1.191 6 Laureth-4 2.00 1.90 7 POE (15)glyceryl monolaurate 2.00 1.90 8 Butylated hydroxytoluene 0.02 0.02 9Retinoic acid (tretinoin) 0.025 0.024 10 Methyl paraben 0.20 0.19 11Aerosol Base (Items 1-10) 100.00 95.00 12 Hydrocarbon propellant NIL5.00 Total 100.00 100.00

Items 1-5 are added stepwise to mixing vessel A. Items 6-10 are addedstepwise to mixing vessel B. While stirring, Phase B is added to Phase Aand mixed until uniform. The Aerosol Base (Item 11) is added to anaerosol can and a valve is secured onto the aerosol can. A propellant(Item 12) is added to the Aerosol Package (i.e., aerosol can with valvecontaining Aerosol Base). The Aerosol Package is placed into a 55° C.water bath for 1-2 minutes, then shaken well and cooled to roomtemperature. The Aerosol Package is shaken immediately prior todispensing.

Example 12

This example illustrates non-alcoholic and alcoholic foam compositionsof the present invention comprising a combination of clindamycinphosphate and benzoyl peroxide.

NON-ALCOHOLIC CLINDAMYCIN/BENZOYL PEROXIDE FOAM % w/w % w/w (without(with ITEM INGREDIENT propellant) propellant) 1 Purified water 86.3982.07 2 Disodium EDTA 0.50 0.47 3 Clindamycin phosphate 1.25 1.19 4Laureth-4 4.00 3.80 5 Methyl paraben 0.20 0.19 6 Benzoyl Peroxide (75%)6.66 6.33 7 Xanthan gum 1.00 0.95 8 Aerosol Base (Items 1-7) 100.0095.00 9 Hydrocarbon propellant NIL 5.00 Total 100.00 100.00

ALCOHOLIC CLINDAMYCIN/BENZOYL PEROXIDE FOAM % w/w % w/w (without (withITEM INGREDIENT propellant) propellant) 1 Purified water 76.38 72.56 2Ethanol 10.00 9.50 3 Disodium EDTA 0.50 0.48 4 Clindamycin phosphate1.25 1.19 5 Laureth-4 4.00 3.80 6 Methyl paraben 0.20 0.19 7 BenzoylPeroxide (75%) 6.67 6.33 8 Xanthan gum 1.00 0.95 9 Aerosol Base (Items1-8) 100.00 95.00 10 Hydrocarbon propellant NIL 5.00 Total 100.00 100.00

NON-ALCOHOLIC CLINDAMYCIN/BENZOYL PEROXIDE FOAM % w/w % w/w (without(with ITEM INGREDIENT propellant) propellant) 1 Purified water 79.7275.73 2 Disodium EDTA 0.50 0.48 3 Clindamycin phosphate 1.25 1.19 4Laureth-4 4.00 3.80 5 Methyl paraben 0.20 0.19 6 Benzoyl Peroxide (75%)13.33 12.66 7 Xanthan gum 1.00 0.95 8 Aerosol Base (Items 1-7) 100.0095.00 9 Hydrocarbon propellant NIL 5.00 Total 100.00 100.00

ALCOHOLIC CLINDAMYCIN/BENZOYL PEROXIDE FOAM % w/w % w/w (without (withITEM INGREDIENT propellant) propellant) 1 Purified water 69.72 66.23 2Ethanol 10.00 9.50 3 Disodium EDTA 0.50 0.48 4 Clindamycin phosphate1.25 1.19 5 Laureth-4 4.00 3.80 6 Methyl paraben 0.20 0.19 7 BenzoylPeroxide (75%) 13.33 12.66 8 Xanthan gum 1.00 0.95 9 Aerosol Base (Items1-8) 100.00 95.00 10 Hydrocarbon propellant NIL 5.00 Total 100.00 100.00

Example 13

This example illustrates a large-scale production of the clindamycinphosphate foam compositions of the present invention.

Two mixing vessels were used for compounding and manufacturing. Onestainless steel tank was used to prepare an ethanolic phase solutioncontaining the excipients (cetyl alcohol, stearyl alcohol, polysorbate60, and propylene glycol). A second stainless steel tank was used toprepare an aqueous solution of the active agent and potassium hydroxide.Water and ethanol were first dispensed into their respective tanks,weighed, and the components were then added. The solutions were mixeduntil each component had dissolved before adding the next. Both phaseswere then transferred to filling vessels. The aqueous phase was filteredthrough a 0.2 micron filter prior to transferring to the filling vessel.Each filling vessel was connected to a 10 micron filter prior to thefilling ram on the filling line and delivery was controlled through apositive displacement diaphragm pump. An aliquot of each solution phasewas independently dispensed into each can and the can was subsequentlyvacuum crimped and sealed. A metered amount of propellant was theninjected via the valve to complete the formulation. Each can was thenleak tested before final placement of the actuator and cap, inkjetlabeling, and secondary packaging.

As noted above, separate preparations of an ethanolic solution and anaqueous solution were used for the preparation of the clindamycinphosphate foam composition. Ethanol is used for rapid and completedissolution of cetyl alcohol and stearyl alcohol, which have low watersolubility. Polysorbate 60 and propylene glycol are liquids that aremiscible in ethanol and water. The active compound is a dry solid anddissolves readily in water. The potassium hydroxide solution is added toadjust the pH.

Example 14

This example describes a foam quality rating scale and a range ofexperiments that can be conducted to characterize foam products in aqualitative and quantitative manner.

In this particular example, foams are rated according to the observablephysical characteristics, such as a visual aid, of foam samples:

-   -   1. Liquid—characterized as being a low viscosity fluid that        readily flows away from the dispensing area when dispensed.        “Liquid” may additionally have the presence of minute bubbles        and as such would have an appearance similar to a carbonated        beverage. Typically, “Liquid” would have similar flow properties        to a sample of water or milk dispensed on to a similar        substrate.    -   2. Runny Foam—characterized as being a three-dimensional,        semi-solid foam structure that readily flows away from the        dispensing area when dispensed. Generally, “Runny Foam” has a        relatively large bubble size and is typically less than 10 mm in        diameter. Typically, “Runny Foam” would exhibit similar flow        characteristics to foam on the top of a milkshake.    -   3. Soft Foam—characterized as being a three-dimensional,        semi-solid foam structure that does not readily flow away from        the dispensing area when dispensed. Generally, “Soft Foam” has a        relatively large bubble size and is typically less than 5 mm in        diameter. Typically, “Soft Foam” would exhibit similar flow        characteristics to whipped egg whites.    -   4. Creamy Foam—characterized as being a three-dimensional,        semi-solid foam structure that does not readily flow away from        the dispensing area when dispensed. Generally, “Creamy Foam” has        a relatively small bubble size and is typically much less than 1        mm in diameter. Typically, “Creamy Foam” would exhibit similar        flow characteristics to whipped cream/shaving cream.    -   5. Crisp Foam—characterized as being a three-dimensional,        semi-solid foam structure that does not readily flow away from        the dispensing area when dispensed. Generally, “Crisp Foam” has        a relatively small bubble size and is typically much less than 1        mm in diameter. Typically, “Crisp Foam” would exhibit similar        flow characteristics to a loosely packed snowball and would        exhibit similar tensile properties such as being brittle (i.e.,        can be readily pulled apart) and have substantially “solid        characteristics.”

General physical appearance of the foam is described using the foamrating scale over a range of temperatures.

Bubble size and average bubble size are measured visually with asuitable reference measurement scale over a range of temperatures.Techniques include: (i) visual, e.g., estimating bubble size relative toa metric scale; and (ii) microscopic, e.g., estimating bubble size usinga calibrated eyepiece graticule.

Foam viscosity is measured with a suitable viscosity measuring device.Techniques include: (i) Brookfield Synchro-lectric rotating spindleviscometer with Ultra-low viscosity adapter, where liquefied foam isintroduced into the temperature-controlled device and viscosity ismeasured at a range of temperatures; and (ii) Brookfield Cone & PlateViscometer, where samples of foam are introduced between the cone andplate and the rheology of the foam is determined over a range of shearrates and temperatures.

Foam density is measured with a suitable density determinationapparatus. Techniques include: (i) pycnometer/weight per gallon cup,where foam at fixed temperatures is carefully introduced into afixed-volume vessel of known volume and mass; and (ii) Electronicdensity/specific gravity meter, where a slow stream of foam at fixedtemperatures is introduced into a flow-through cell and the density isdetermined by the oscillating body method.

Foam expansion rate is the determination of the rate at which the foamexpands. Suitable techniques for measuring the expansion rate include:(i) visual, where foam is introduced into a measuring cylinder and theoccupied volume is recorded over time at a range of temperatures, (ii)visual/timelapse photography, where the cross-sectional area/volume isestimated over a relatively short time-scale, and (iii) visual/rate ofgrowth, where a fixed quantity of foam is introduced into a constantdiameter capillary tube and the time at which the foam passes calibratedmarks is recorded.

Product clarity is described by visual inspection of the product. Thisinvolves preparing formulations in transparent, plastic-coated glassaerosol vessels and storing the products in an incubator capable ofcontrolled temperature storage over the range of from 0° C. to 30° C.The temperature is reduced (from the minimum storage temperature atwhich the product is clear) at a rate of approximately −1° C./day andthe observations are recorded. Once the lowest temperature has beenreached the temperature is increased at the rate of +1° C./day and theobservations are recorded.

The “minimum use temperature” is the lowest recorded temperature (i.e.,increasing temperature) where precipitated matter has redissolved.

Flow rate is a measurement of the flow characteristics. This techniqueinvolves dispensing foam at a range of temperatures onto acontrolled-temperature surface on an incline (or perhaps by sprayingonto a vertical surface) and the distance the liquid travels from thedispensing area and time taken are recorded.

The foregoing discussion of the invention has been presented forpurposes of illustration and description. The foregoing is not intendedto limit the invention to the form or forms disclosed herein. Althoughthe description of the invention has included description of one or moreembodiments and certain variations and modifications, other variationsand modifications are within the scope of the invention, e.g., as may bewithin the skill and knowledge of those in the art, after understandingthe present disclosure. It is intended to obtain rights which includealternative embodiments to the extent permitted, including alternate,interchangeable, and/or equivalent structures, functions, ranges, orsteps to those claimed, whether or not such alternate, interchangeable,and/or equivalent structures, functions, ranges, or steps are disclosedherein, and without intending to publicly dedicate any patentablesubject matter.

1. A topical delivery foam composition in a pressurized container, saidcomposition comprising: up to 15% of at least one pharmaceuticallyactive agent, wherein the at least one pharmaceutically active agentcomprises a combination of benzoyl peroxide and clindamycin or a salt orester thereof; from about 83% to about 97.9% w/w of a quick-breakingfoaming agent comprising water and a surfactant; and from about 2% toabout 7% w/w of an aerosol propellant selected from the group consistingof a hydrocarbon, a chlorofluorocarbon, dimethyl ether,hydrofluorocarbons and a mixture thereof, wherein said composition is aquick-breaking foam after release from said container, and wherein saidquick-breaking foaming agent comprises about 80% to about 95% w/w waterand about 0% of a C₁-C₆ alcohol, based on the total weight of thecomposition.
 2. The topical delivery foam composition of claim 1,wherein said clindamycin is clindamycin phosphate.
 3. (canceled)
 4. Thetopical delivery foam composition of claim 1, wherein said surfactant isselected from the group consisting of a block co-polymer, fatty acidethoxylates, fatty alcohol ethoxylates, polysorbates and glycerol esterethoxylates.
 5. The topical delivery foam composition of claim 4,wherein said surfactant is a block co-polymer.
 6. The topical deliveryfoam composition of claim 5, wherein said block co-polymer is apoloxamer.
 7. The topical delivery foam composition of claim 1, whereinsaid surfactant is selected from the group consisting of Polysorbate 20,Polysorbate 60, Polysorbate 80, Laureth-4, Laureth-23, POE(15) glycerolmonolaurate, and mixtures thereof.
 8. The topical delivery foamcomposition of claim 1, wherein said surfactant is present in an amountof from about 0.1% to about 10% w/w.
 9. The topical delivery foamcomposition of claim 8, wherein said surfactant is present in an amountof from about 0.1% to about 6% w/w.
 10. The topical delivery foamcomposition of claim 1, wherein said quick-breaking foaming agentfurther comprises a pH adjusting agent.
 11. The topical delivery foamcomposition of claim 10, wherein said pH adjusting agent is present inan amount sufficient to adjust the pH of the composition to betweenabout 4.0 to about 6.5.
 12. The topical delivery foam composition ofclaim 10, wherein said pH adjusting agent is a buffer.
 13. The topicaldelivery foam composition of claim 12, wherein said buffer is selectedfrom the group consisting of citrate/citric acid, acetate/acetic acid,phosphate/phosphoric acid, formate/formic acid, propionate/propionicacid, lactate/lactic acid, carbonate/carbonic acid and ammonium/ammoniabuffer.
 14. The topical delivery foam composition of claim 1, whereinsaid quick-breaking foaming agent contains about 0% of an emollient. 15.The topical delivery foam composition of claim 1, wherein saidcomposition further comprises xanthan gum.
 16. A topical delivery foamcomposition in a pressurized container, said composition comprising:benzoyl peroxide and clindamycin or a salt or ester thereof; aquick-breaking foaming agent comprising: a) water present in an amountfrom about 80% to about 95% w/w based on the total weight of thecomposition, and b) a surfactant, wherein the quick-breaking foamingagent contains about 0% of a C₁-C₆ alcohol based on the total weight ofthe composition; and an aerosol propellant selected from the groupconsisting of a hydrocarbon, a chlorofluorocarbon, dimethyl ether,hydrofluorocarbons and a mixture thereof, wherein said composition is aquick-breaking foam after release from said container.
 17. The topicaldelivery foam composition of claim 16, wherein said surfactant isselected from the group consisting of a block copolymer, fatty acidethoxylates, fatty alcohol ethoxylates, polysorbates and glycerol esterethoxylates.
 18. The topical delivery foam composition of claim 16,wherein said surfactant is selected from the group consisting ofPolysorbate 20, Polysorbate 60, Polysorbate 80, Laureth-4, Laureth-23,POE(15) glycerol monolaurate, and mixtures thereof.
 19. The topicaldelivery foam composition of claim 16, wherein said surfactant ispresent in an amount of from about 0.1% to about 10% w/w.
 20. Thetopical delivery foam composition of claim 19, wherein said surfactantis present in an amount of from about 0.1% to about 6% w/w.
 21. Thetopical delivery foam composition of claim 16, wherein saidquick-breaking foaming agent further comprises a pH adjusting agent. 22.The topical delivery foam composition of claim 21, wherein said pHadjusting agent is present in an amount sufficient to adjust the pH ofthe composition to between about 4.0 to about 6.5.
 23. The topicaldelivery foam composition of claim 21, wherein said pH adjusting agentis selected from the group consisting of a base and a buffer.
 24. Thetopical delivery foam composition of claim 23, wherein said pH adjustingagent is a buffer.
 25. The topical delivery foam composition of claim24, wherein said buffer is selected from the group consisting ofcitrate/citric acid, acetate/acetic acid, phosphate/phosphoric acid,formate/formic acid, propionate/propionic acid, lactate/lactic acid,carbonate/carbonic acid and ammonium/ammonia buffer.
 26. The topicaldelivery foam composition of claim 25, wherein said buffer iscitrate/citric acid.
 27. The topical delivery foam composition of claim16, wherein said quick-breaking foaming agent contains about 0% of anemollient.
 28. The topical delivery foam composition of claim 16,wherein said composition further comprises xanthan gum.
 29. The topicaldelivery foam composition of claim 21, wherein said composition furthercomprises xanthan gum.
 30. The topical delivery foam composition ofclaim 1, wherein said aerosol propellant is a hydrocarbon propellant.31. The topical delivery foam composition of claim 16, wherein saidaerosol propellant is a hydrocarbon propellant.